Carvedilol is an active substance, which has very low water solubility. At pH values in the pharmaceutically relevant range of 1 to 8 the solubility of carvedilol in aqueous media is from about 0.01 mg/ml to about 1 mg/ml. The solubility depends on the pH value as carvedilol is a weak base, i.e. the solubility is theoretically larger in an acid medium than in a basic medium. More specifically, it is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH1.1) and intestinal fluid (simulated, TS without pancreatin, pH 7.5).
Furthermore, carvedilol is subject to degradation under formation of various generally unwanted degradation products. Carvedilol is normally employed in pharmaceutical compositions in the form of a racemic mixture. It is known that both the R(+) carvedilol and the S(−) carvedilol have a therapeutic effect (cf. below).
Carvedilol may exist in at least two different crystalline forms, normally denoted from I and form II. Form II has a melting point of about 114-115° C., whereas form I has a melting point of about 123-124° C. (EP-A-0 893 440). Form I is described to be thermodynamically stable.
Thus, carvedilol is a substance with solubility and stability problems and, furthermore, such problems normally indicate that the bioavailability is low.
Furthermore, many crystalline, therapeutically active substances have a very limited solubility in aqueous medium such as, e.g., body fluids. It is well known that changing a crystalline compound into its amorphous state will substantially increase the aqueous solubility of the compound.
An amorphous state of an active substance may be obtained by melting the active substance, holding it in the molten state for a certain period of time and then cooling it to an amorphous solid. Such a method is limited to particular active substances that can produce stable amorphous solids that are not degraded by the heating step.
Accordingly, there is a need for novel compositions comprising carvedilol or other active substances having a low water solubility in which the solubility, stability and/or bioavailability is improved.